Abstract

Impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-specific deficiency of long-chain acyl-CoA synthetase-1 (ACSL1). ACSL1 deficiency caused a 91% loss of ACSL specific activity and 60-85% decreases in muscle FA oxidation. Acsl1M-/- mice were more insulin-sensitive, and during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1M-/- mice ran only 48% as far as controls. At the time that Acsl1M-/- mice were exhausted but control mice continued to run, liver and muscle glycogen and triacylglycerol stores were similar in both genotypes; however, Acsl1M-/- plasma glucose concentrations were ∼40 mg/dl, whereas control glucose levels were ∼90 mg/dl. Excess use of glucose and the likely use of amino acids for fuel within muscle depleted glucose reserves and diminished substrate availability for hepatic gluconeogenesis. Surprisingly, the content of muscle acyl-CoA at exhaustion was markedly elevated, indicating that acyl-CoAs synthesized by other ACSL isoforms were not available for β-oxidation. This compartmentalization of acyl-CoAs resulted in both an excessive glucose requirement and severely compromised systemic glucose homeostasis.